Imino sugars for flavivirus infections of bioterror

用于生物恐怖黄病毒感染的亚氨基糖

• 批准号: 8040427
• 负责人: Timothy M Block
• 金额: $ 34.59万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-22 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8040427
• 关键词: Animal Model; Animals; Antiviral Agents; Antiviral Response; Biochemical; Biochemical Markers; Biological Assay; Biological Markers; Cattle; Cell Culture System; Cell physiology; Chemical Structure; Chemicals; Clinical; Clinical Pathways; Dengue Virus; Development; Diarrhea; Disease; Drug Formulations; Encephalitis; Encephalitis Viruses; Family; Flaviviridae; Flavivirus; Flavivirus Infections; Genes; Glucosidase Inhibitor; Goals; Growth; Hamsters; Host Defense; Human; Human Cell Line; In Vitro; Interferons; Japanese Encephalitis Viruses; Japanese encephalitis virus; Kyasanur Forest disease virus; Lead; Licensing; Life Cycle Stages; Ligase; Omsk hemorrhagic fever virus; Oral; Pathway interactions; Pestivirus; Phase; Public Health; Rattus; Relative (related person); Rodent; Safety; Secondary to; Series; Structure; Structure-Activity Relationship; Surrogate Markers; System; Testing; Therapeutic; Tick-Borne Encephalitis Virus; Tick-Borne Encephalitis Viruses; Time; Toxic effect; Vero Cells; Viral; Viral Hemorrhagic Fevers; Virus; Virus Diseases; West Nile virus; Work; Yellow fever virus; arm; base; design; genotoxicity; glucosidase; in vivo; indexing; inhibitor/antagonist; meetings; member; mouse model; pre-clinical; preclinical toxicity; safety study; safety testing; sound; sugar; tissue culture

DESCRIPTION (provided by applicant): This is an application to develop an orally available imino sugar for the treatment of flaviviruses infections of bioterror concern, with a focus upon West Nile Encephalitis virus (WNEV) and Dengue Viruses (DV). Our lead compound, the imino sugar, N, -nonyl-deoxynorjirimycin (NN-DNJ) has been shown to have efficacy in animal models of flavivirus infection. Although sound in mechanism, development of this compound was limited by formulation and toxicity issues. Therefore, a compound with a superior activity and toxicity profile will be sought. A new mechanism of action (MOA) and structure activity relationship (SAR) information will be used to rationally design imino sugars; we call alkovirs and glucovirs. These will first be tested for the ability to inhibit bovine viral diarrhea (BVDV) in yield reduction assays, since it shares the same step as other flaviviruses in the virus life cycle that is sensitive to the imino sugars. Compounds that show promise in BVDV testing will be selected for in vitro and in vivo testing against WNV and DV. If compounds are found that are superior to NN-DNJ on the basis of set criteria of selectivity and tolerability in tissue culture and animal models of DV and WNEV, they will replace NN-DNJ in the pre-clinical and clinical development path.

描述（由申请人提供）：本申请旨在开发一种口服可用的亚氨基糖，用于治疗生物恐怖关注的黄病毒感染，重点是西尼罗河脑炎病毒（WNEV）和登革热病毒（DV）。我们的先导化合物，亚氨基糖，N，-壬基-脱氧去甲野尻霉素（NN-DNJ）已被证明在黄病毒感染的动物模型中具有疗效。虽然机制合理，但该化合物的开发受到制剂和毒性问题的限制。因此，将寻求具有上级活性和毒性特征的化合物。一种新的作用机制（MOA）和结构活性关系（SAR）信息将用于合理设计亚氨基糖;我们称之为alkovir和glucovir。将首先在产量降低试验中检测这些病毒抑制牛病毒性腹泻（BVDV）的能力，因为其与病毒生命周期中对亚氨基糖敏感的其他黄病毒具有相同的步骤。将选择在BVDV检测中显示前景的化合物用于抗WNV和DV的体外和体内检测。如果基于DV和WNEV的组织培养和动物模型中的选择性和耐受性的设定标准，发现化合物上级NN-DNJ，则它们将在临床前和临床开发路径中取代NN-DNJ。

项目成果

Small molecule inhibitors of ER α-glucosidases are active against multiple hemorrhagic fever viruses.

• DOI: 10.1016/j.antiviral.2013.03.023
• 发表时间: 2013-06
• 期刊: ANTIVIRAL RESEARCH
• 影响因子: 7.6
• 作者: Chang, Jinhong;Warren, Travis K.;Zhao, Xuesen;Gill, Tina;Guo, Fang;Wang, Lijuan;Comunale, Mary Ann;Du, Yanming;Alonzi, Dominic S.;Yu, Wenquan;Ye, Hong;Liu, Fei;Guo, Ju-Tao;Mehta, Anand;Cuconati, Andrea;Butters, Terry D.;Bavari, Sina;Xu, Xiaodong;Block, Timothy M.
• 通讯作者: Block, Timothy M.

RO 90-7501 enhances TLR3 and RLR agonist induced antiviral response.

• DOI: 10.1371/journal.pone.0042583
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Guo F;Mead J;Aliya N;Wang L;Cuconati A;Wei L;Li K;Block TM;Guo JT;Chang J
• 通讯作者: Chang J

Design, synthesis, and biological evaluation of N-alkylated deoxynojirimycin (DNJ) derivatives for the treatment of dengue virus infection.

• DOI: 10.1021/jm300171v
• 发表时间: 2012-07-12
• 期刊: JOURNAL OF MEDICINAL CHEMISTRY
• 影响因子: 7.3
• 作者: Yu, Wenquan;Gill, Tina;Wang, Lijuan;Du, Yanming;Ye, Hong;Qu, Xiaowang;Guo, Ju-Tao;Cuconati, Andrea;Zhao, Kang;Block, Timothy M.;Xu, Xiaodong;Chang, Jinhong
• 通讯作者: Chang, Jinhong